# Cytotoxic Lung Endothelial Amyloids

> **NIH NIH F31** · UNIVERSITY OF SOUTH ALABAMA · 2020 · $9,107

## Abstract

PROJECT SUMMARY/ABSTRACT
Pulmonary endothelial barrier integrity is vital for efficient gas exchange and to prevent the hematogenous
dissemination of respiratory pathogens. Pseudomonas aeruginosa, a predominant agent of nosocomial
pneumonia, breaches the endothelial barrier by inducing junctional complex disruption leading to alveolar
flooding and hypoxemia. Here, we propose to study a previously unidentified, novel disease process defined by
the interaction of the common nosocomial pathogen, P. aeruginosa, with the host endothelium. P. aeruginosa
utilizes a Type III Secretion System (T3SS) to inject cytotoxic exoenzymes directly into the host cell. Exoenzyme
Y (ExoY), a T3SS effector expressed by ~90% of clinical P. aeruginosa strains, causes marked increases in
cytosolic cGMP, cUMP, and cAMP. The increase in cAMP facilitates the phosphorylation of an endothelial tau,
which dissociates from microtubules, followed by microtubule collapse, interendothelial gap formation, and
increased permeability. Hyperphosphorylated tau then coalesces into cytotoxic tau oligomers that are released
into the extracellular milieu. These cytotoxic tau oligomers are transmissibleand self-propagating amyloid prions.
The respective roles of cGMP and cUMP are currently unknown, although preliminary data establishes both a
temporal and spatial correlation between the increase in ExoY-generated cUMP and oligomeric tau release from
PMVECs. The cUMP signal in the bulk cytosol closely coincides with both the reduction of cytosolic tau and the
concomitant increase of extracellular tau. Thus, an ExoY-instigated increase in cUMP is implicated in the export
of cytotoxic tau. Furthermore, within the context of neurodegenerative disease, the degradation and recycling
pathway of autophagy is often pathologically constrained thereby preventing the breakdown of excess or
dysregulated amyloids. Following the inhibition of autophagic flux, dysregulated amyloids accumulate and
oligomerize. Clearance of nascent tau oligomers is often facilitated via exosomal and/or secretion mediated
export. Concordant with our observations, ExoY has recently been implicated in the suppression of the innate
immune response via the inhibition of transforming growth factor-β-activating kinase 1 (TAK1) which has also
been reported to obstruct autophagy. Taken together, ExoY suppression of TAK1 in PMVECs may contribute to
the inhibition of autophagy and the production of infection-induced tau prions. Therefore, this proposal tests the
hypothesis that ExoY-induced cUMP contributes to the suppression of autophagic flux thereby promoting the
generation and release of cytotoxic tau that transmissibly disrupts interendothelial junctions and promotes
perm eability.
.

## Key facts

- **NIH application ID:** 10012762
- **Project number:** 5F31HL147512-02
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** Sarah B. Voth
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $9,107
- **Award type:** 5
- **Project period:** 2019-09-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012762

## Citation

> US National Institutes of Health, RePORTER application 10012762, Cytotoxic Lung Endothelial Amyloids (5F31HL147512-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10012762. Licensed CC0.

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